Inflammation and excitoxicity appear to be pivotal in CNS trauma, but effective strategies for targeting these aspects of secondary injury have been elusive. Proinflammatory cytokines appear to have complex and sometimes contradictory roles in CNS injury and repair. Similarly, glutamate receptors are responsible for excitotoxic death of neurons and glia in injury, but are also essential for normal CNS function, and have been implicated in recovery after injury. The pro-inflammatory cytokine tumor necrosis factor-alpha (TNFa) has recently been shown to have a unique and critical role in the modulation of normal neuronal glutamate synaptic transmission (Beattie et ai, 2002;Stellwagen and Malenka, 2006;Aizenman and Pratt, 2008), and also to exacerbate excitotoxic cell death (Hermann et ai, 2001;Beattie, 2004). We have identified TN Fa-mediated trafficking of GluR2-lacking, Ca++-permeable AMPA receptors (CP-AMPARs) as a novel and perhaps 'nodal'link between injury-induced inflammation and excitotoxicity. TN Fa increases excitotoxic cell death in vitro, and enhances neuronal death after spinal cord injury (SCI). Further, reducing GluR2- lacking AMPAR-insertion into neuronal membranes by blocking TNFa after SCI, results in reduced neuronal death, reduced white matter damage, and better outcomes in a cervical injury model of SCI.